Serotonin (5-hydroxytryptamine, 5-HT) is a major neurotransmitter eliciting effects via a multiplicity of receptors. To date, at least fifteen different 5-HT receptors have been identified, largely as the result of cloning cDNA's, and these receptors have been grouped into seven families (5-HT1 through 5-HT7) (Hoyer, D. et al. Pharmacol. Biochem. Behav. 2002, 71, 533-554).
Fourteen of the fifteen cloned 5-HT receptors are expressed in the brain. 5-HT is implicated in many disease states, particularly conditions of the central nervous system including; depression, anxiety, schizophrenia, eating disorders, obsessive compulsive disorder, learning and memory dysfunction, migraine, chronic pain, sensory perception, motor activity, temperature regulation, nociception, sexual behavior, hormone secretion, and cognition.
The identification of multiple 5-HT receptors has provided the opportunity to characterize existing therapeutic agents thought to act via the serotonergic system. Consequently, this has led to the realization that many drugs have non-selective properties (Roth, B. L. et al. Neuroscientist 2000, 6(4), 252-262). For example, the antipsychotic drugs, clozapine, chlorpromazine, haloperidol and olanzapine exhibit affinities for multiple serotonin receptors in addition to other families of receptors. Similar behavior has been noted for antidepressants, including imipramine, nortriptaline, fluoxetine and sertraline. Similarly, the anti-migraine agent sumatriptan exhibits high affinity for several serotonin receptors. While the lack of selectivity often contributes to a favorable therapeutic outcome, it can also cause undesirable and dose-limiting side effects (Stahl, S. M. Essential Psychopharmacology, 2nd ed., Cambridge University Press, Cambridge, U.K., 2000). Thus, the inhibition of serotonin and norepinephrine uptake together with 5-HT2 receptor blockade is responsible for the therapeutic effects of the tricyclic antidepressants. In contrast, their blockade of histamine H1, muscarinic and alpha-adrenergic receptors can lead to sedation, blurred vision and orthostatic hypertension respectively. Likewise, the atypical antipsychotics, including olanzapine and clozapine, are considered to have positive therapeutic effects attributable to their actions at 5-HT2, D2 and 5-HT, receptors. Conversely, their side effect liability is due to their affinities for a range of dopaminergic, serotonergic and adrenergic receptors.
More selective ligands therefore have the potential to ameliorate untoward pharmacologies and provide novel therapies. More importantly the ability to obtain compounds with known receptor selectivities affords the prospect to target multiple therapeutic mechanisms and improve clinical responses with a single drug. There remains a need for potent serotonin receptor modulators with desirable pharmaceutical properties.
4-Phenyltetrahydropyrido[4,3-d]pyrimidines with utility in the treatment of gastrointestinal diseases are described by Sanfilippo et al. in U.S. Pat. No. 5,137,890 and Eur. J. Med. Chem. 1992, 27(7), 655-661. Fused 2-aminopyrimidines have been disclosed as glycogen synthase kinase 3 (GSK3) inhibitors for the treatment of Alzheimer's disease and other neurodegenerative disorders, traumatic brain injury, and bipolar disorder in Intl. Pat. Appl. Publ. WO 2001/044246.
Indole and pyrazole compounds have been described as serotonin modulators in Intl. Pat. Appl. Publ. WO 2005/040169 (Janssen Pharmaceutica N.V., May 6, 2005). Pyrimidine compounds have been described as serotonin modulators in U.S. Pat. Appl. Publ. No. US 2007/032481 (Janssen Pharmaceutica N.V., Feb. 8, 2007).